Free Water in White Matter Differentiates MCI and AD From Control Subjects

Matthieu Dumont; Maggie Roy; Pierre-Marc Jodoin; Felix C Morency; Jean-Christophe Houde; Zhiyong Xie; Cici Bauer; Tarek A Samad; Koene R A Van Dijk; James A Goodman; Maxime Descoteaux; Alzheimer's Disease Neuroimaging Initiative

doi:10.3389/fnagi.2019.00270

Free Water in White Matter Differentiates MCI and AD From Control Subjects

Front Aging Neurosci. 2019 Oct 2:11:270. doi: 10.3389/fnagi.2019.00270. eCollection 2019.

Authors

Affiliations

¹ Imeka Solutions, Inc., Sherbrooke, QC, Canada.
² Sherbrooke Connectivity Imaging Lab, University of Sherbrooke, Sherbrooke, QC, Canada.
³ VITAlab, University of Sherbrooke, Sherbrooke, QC, Canada.
⁴ Digital Medicine & Translational Imaging, Early Clinical Development, Pfizer Inc., Cambridge, MA, United States.
⁵ Department of Biostatistics and Data Science, The University of Texas Health Science Center at Houston, Houston, TX, United States.
⁶ Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States.

Abstract

Recent evidence shows that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple but powerful whole-brain FW measure designed for easy translation to clinical settings and potential use as a priori outcome measure in clinical trials. These simple FW measures use a "safe" white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WM _safe) near ventricles and sulci. We investigated if FW inside the WM _safe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

Keywords: Alzheimer disease; diffusion MRI; diffusion tensor imaging; free water; mild cognitive impairment; neuroinflammation; white matter; white matter hyper intensity.